Hormone replacement therapy (HRT) is the most commonly prescribed medication for the alleviation of menopausal symptoms. Unopposed estrogen replacement therapy increases the risk of developing endometrial cancer by 120% for every 5 years of use. To eliminate this risk in women with a uterus, the addition of progesterone to HRT in the form of combined estrogen/progesterone replacement has been implemented. Considerable evidence now indicates that the addition of synthetic progestins to HRT increases the risk of breast cancer as well as many other deleterious side effects. In response to the problems associated with HRT, millions of women are exploring the use of botanicals and dietary supplements for the alleviation of climacteric symptoms. However, the use of botanicals with only plant-derived estrogens in the absence of progestins might increase the risk for developing endometrial cancer similar to estrogen alone. Two common supplements, hops and red clover, contain phytoestrogens that bind and activate estrogen receptors. Interestingly, when hops and red clover are given orally to ovariectomized rats, uterine weights are not significantly increased in animals treated with a crude extract but are significantly increased in animals given an equivalent dose of the pure phytoestrogen. The hypothesis of this grant proposal is that selective natural progesterone compounds can be identified from botanical extracts to generate a combined phytoestrogen-phytoprogestin alternative to traditional hormone replacement therapy. The presence of both estrogen and progesterone receptor agonists in one botanical extract may provide both the benefits of estrogens for alleviation of menopausal symptoms and the progesterone necessary to combat formation of uterine cancers. Selective and safer progestins might also be identified from botanical sources improving the overall behavior of the progestin used in HRT. In order to provide support for this hypothesis the following specific aims are proposed: Aim 1. Do botanical extracts contain phytoprogestins and what are the pure compounds responsible for the progesterone-like activity? Aim 2. Are phytoprogestins specific and selective for uterine progesterone receptors? Aim 3. Are phytoprogestins protective against uterine hyperplasia in an ovariectomized rat model? These studies will provide a clear justification for the use of botanicals that have the possibility of providing both estrogen and progestin-like activity but with more selective and safer profiles for the treatment of menopausal symptoms. Women are already taking phytoestrogens for menopausal symptoms, and incorporation of progestins may prevent hyperplasia and cancer of the uterus. PUBLIC HEALTH RELEVANCE: Women are already taking phytoestrogens in botanical extracts for menopausal symptoms, and the incorporation of progestins may prevent hyperplasia and cancer of the uterus. As women search for more potent alternative estrogens to satisfy the need for menopausal symptom alleviation, the chance for hyperplasia in the uterus increases and makes the characterization of novel phytoprogestins crucial.